Adenovirus type 35, but not type 5, stimulates NK cell activation via plasmacytoid dendritic cells and TLR9 signaling

In hematopoietic stem cell transplant (HSCT) recipients, disseminated adenoviral infections during the first two months after HSCT can lead to severe complications and fatal outcome. Since NK cells are usually the first lymphocytes to reconstitute after HSCT and have been implicated in the clearance of adenovirus-infected cells, it was investigated whether NK cells are activated by adenovirus in vitro. Exposure of PBMC to human adenovirus type 5 (HAdV5) or HAdV35 resulted in the up-regulation of the activation marker CD69 on NK cells and enhanced the cytolytic activity of NK cells. HAdV5-induced NK cell activation relied on the contribution of T cells as the depletion of T cells from PBMC abolished NK cell activation. In contrast, NK cell activation in response to HAdV35 occurred in the absence of T cells. Plasmacytoid dendritic cells (pDC) were necessary and sufficient to mediate NK cell activation. HAdV35 induced significantly more interferon-α (IFN-α) production by pDC than HAdV5. The increased IFN-α production and NK cell activation correlated with a higher infection efficiency of viruses with the type 35 fiber. The IFN-α response of pDC was enhanced by the presence of NK cells, suggesting a reciprocal interaction between pDC and NK cells. Incubation with a TLR9 antagonist impaired the IFN-α production by pDC as well as NK cell activation, implying that TLR9 signaling is critically involved in the IFN-α response of pDC and NK cell activation after HAdV35 exposure. In conclusion, two human adenovirus serotypes from two different species differ considerably in their capacity to stimulate pDC and NK cells.     

TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2(V617F) expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2(V617F)-positive MPN. Altogether our data are consistent with a model where JAK2(V617F) promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.     

Aetiological agents of ventilator-associated pneumonia and its resistance pattern – a threat for treatment

Background

Ventilator-associated pneumonia (VAP) is a common type of nosocomial pneumonia encountered in intensive care units. There are several aetiological agents which make treatment challenging. Improper antibiotic treatment of ventilated patients may lead to the emergence of multidrug resistant (MDR) pathogens.

Method

A prospective study was performed over a period of 20 months. Our study had two arms: the first, ‘Incidence and risk factors of VAP in a tertiary care hospital’ was the subject of an earlier publication; we therefore present the second investigative arm in this work. The aetiological agents of patients on mechanical ventilation (MV) were identified by standard bacteriological method. The susceptibility pattern was evaluated by Kirby-Bauer disc diffusion method. Extended spectrum beta lactamase (ESBL) testing was performed by combination disc method, and metallo-beta lactamase (MBL) testing was performed by EDTA disk synergy test (EDS).

Results

Late-onset VAP was associated with Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli, while early-onset VAP was commonly caused by members of Enterobacteriaceae, Candida albicans and Staphylococcus aureus. 72.2 per cent of VAP patients had monomicrobial and 27.8 per cent had polymicrobial infection. Out of the 24 isolates obtained from patients with VAP, seven (29.2 per cent) were MDR pathogens. ESBL and MBL production was detected in 40 per cent and 20 per cent of Klebsiella pneumoniae isolated in our study. Around 50 per cent of isolates associated with late-onset VAP were MDR, while 22.2 per cent isolates obtained from patients with earlyonset VAP were MDR.

Conclusion

VAP is a nosocomial pneumonia that is common among ventilated patients. The aetiological agents vary from common organisms to MDR pathogens that are difficult to treat. A proper knowledge of MDR pathogens and early isolation followed by prevention of prolonged antibiotic therapy can reduce the mortality of late onset VAP.     

Pediatric heart transplantation for anthracycline cardiomyopathy: cancer recurrence is rare.

BACKGROUND: Although anthracycline therapy is invaluable for treating neoplastic disorders, morbidity includes severe cardiomyopathy that leads to heart transplantation. This multicenter study describes the course of children who experienced anthracycline cardiomyopathy (ACM) and who subsequently required heart transplantation. METHODS: We reviewed transplant databases/registries at 4 pediatric heart transplant centers to identify children with ACM who were listed for heart transplantation. We reviewed medical records to determine cancer therapy, clinical course, and outcome. RESULTS: Eighteen patients were listed, and 17 underwent transplantation. Mean age at cancer diagnosis was 6.0 years (SD, 3.7). The mean anthracycline dose was 361 mg/m2 (SD, 110). The median time from cancer diagnosis to listing for heart transplantation was 9.2 years (range, 0.4-15.2 years). Six transplantations were performed in patients who had disease-free intervals of <5 years. Two patients were lost to follow-up, and 8 are alive at 4.9 years (SD, 2.0; range, 1.3-7.4 years) after transplantation. Seven patients died at 4.7 years (SD, 2.0; range, 1.2-7.1 years) after transplantation. One patient had recurrent cancer. One-, 2- and 5-year survivals were 100%, 92%, and 60%, respectively. CONCLUSIONS: Cardiomyopathy that progresses to the need for heart transplantation occurs in patients receiving a wide range of cumulative anthracycline doses. The time from chemotherapy to ACM varies. Outcomes after transplantation are acceptable, and cancer recurrence is rare. Reconsideration of the 5-year disease-free wait period is warranted.     

Purposiveness and leisure-time physical activity in women in early midlife

Physical activity in early midlife has important implications for women's health. The present cross-sectional study investigated the relation of purposiveness to leisure-time physical activity, as mediated by health investment, in a sample of women in early midlife. Participants were 211 women between the ages of 35 and 45 years (mean 40.55 years, SD = 3.11) who responded to the second wave of the study of Midlife Development in the United States. Participants were originally selected by means of a nationally representative random-digit-dialing procedure. A structural equation analysis of data with latent variables was conducted with MPLUS. Purposiveness was indexed by measures of purpose in life, personal growth, and future planning. Health investment was indexed by thought and effort committed to health and the extent to which individuals worked hard to stay healthy. Leisure-time physical activity was indexed by both moderate and vigorous leisure-time activity. Results, controlling for sociodemographic factors, showed that purposiveness was associated with more physical activity and that the relation between purposiveness and leisure-time physical activity was fully mediated by health investment. These results suggest that women with a sense of purpose may be better able to achieve acceptable levels of physical activity.     

BK polyomavirus infection in pediatric heart transplant recipients: a prospective study

BKV infection and nephropathy complicate pediatric HTx, but the incidence and time course of the disease are unknown. We assessed the incidence of BKV infection and its association with kidney dysfunction in pediatric HTx recipients. A single center prospective study compared pediatric (<18 years) HTx recipients, with and without BKV infection, who received an allograft between September 2013 and December 2014. Screening of urine for BKV was performed prior to transplant, and at week 1, and at months 3, 6, 9, 12, and 15 months post‐transplantation. Serum for BKV DNA was assayed if BK viruria was present. Statistics included Fisher's exact test and Student's t test. Twelve patients were enrolled. Two patients were removed per parent request. Two (20%) had BK viruria and one (10%) had BK viremia. No patients developed BKVN. BK viruria was present within 2 months following transplantation. There were no identifiable risk factors for BKV infection and no statistically significant difference in renal function between the groups; however, there was a trend toward worsening renal function in those with BKV infection. BKV infection can occur early following heart transplantation. Screening for BK viruria should be considered in HTx recipients.